Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:30]=2)[C:26]([O:28][CH3:29])=[O:27])O1>>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2F)c1

Procedure:
According to General Method 1A, 5.0 g (20.6 mmol) of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene and 13.53 g (51.44 mmol) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate were reacted. Yield: 3.6 g (58% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)Cc1ccc(Cl)cc1
Yield: 92 %

Procedure:
A solution of 4-chlorobenzylsulfonyl acetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 92% yield.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with THF (15 mL), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.00 g, 3.73 mmol), 3-aminopyridine (351 mg, 3.73 mmol) and sodium tert-butoxide (789 mg, 8.21 mmol). After bubbling nitrogen through the resulting solution for 30 min, Pd2Br2(t-Bu3P)2 (29 mg, 0.037 mmol) was added, and the reaction mixture was stirred at room temperature for 2.5 h. After this time the reaction was partitioned between ethyl acetate (50 mL) and water (50 mL) and filtered. The aqueous layer was separated and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a 35% yield (370 mg) of 112a as a brown solid: mp>250° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.08 (d, 1H, J=2.5 Hz), 8.32 (m, 1H), 8.24 (dd, 1H, J=5.0, 1.5 Hz), 7.40 (s, 1H), 7.36 (dd, 1H, J=8.5, 4.5 Hz), 3.45 (s, 3H); MS (APCI+) m/z 281.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH2:21]([N:8]1[C:4]2[C:3]([O:13][CH3:14])=[C:2]([Br:1])[CH:12]=[CH:11][C:5]=2[N:6]([CH3:10])[C:7]1=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1c(Br)ccc2c1[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Br)ccc2c1n(Cc1ccccc1)c(=O)n2C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A solution of 5-bromo-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (60.0 mg, 0.233 mmol) in N,N-dimethylformamide (2.31 mL) was treated with cesium carbonate (380 mg, 1.17 mmol) and benzyl bromide (99.8 mg, 0.583 mmol) and stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (15% EtOAc/hexanes to 40% EtOAc/hexanes) gave the desired product (73 mg, 90%). LCMS calculated for C16H16BrN2O2 (M+H)+: m/z=347.1, 349.1. found: 347.0, 349.0.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:17])[CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.I.[PH2](O)=O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([Br:17])=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: Brc1ccc2cc3cc(Br)ccc3cc2c1
Temperature: 25 °C

Procedure:
Subsequently, a mixture of 2,6-dibromoanthraquinone (22.41 g, 61.23 mmol), acetic acid (250 mL), 56-58% hydriodic acid (100 mL), and 50% hypophosphorous acid (55 mL) was refluxed for 5 days. The mixture was cooled to RT and poured into ice water (800 mL). The resulting precipitate was filtered, washed with water and ethanol, and recrystallized from toluene (620 mL) to give 2,6-dibromoanthracene: 14.49 g pale yellow flake-like crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[C:22]2[C:23](=[O:41])[N:24]([CH3:40])[C:25]([CH2:38][OH:39])=[C:26]([C:27]3[C:28]([CH3:37])=[C:29]4[C:34](=[CH:35][CH:36]=3)[O:33][CH2:32][CH2:31][CH2:30]4)[C:21]=2[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[C:22]2[C:23](=[O:41])[N:24]([CH3:40])[C:25]([CH:38]=[O:39])=[C:26]([C:27]3[C:28]([CH3:37])=[C:29]4[C:34](=[CH:35][CH:36]=3)[O:33][CH2:32][CH2:31][CH2:30]4)[C:21]=2[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(-c2c(CO)n(C)c(=O)c3c2ccn3Cc2ccccc2)ccc2c1CCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(-c2c(C=O)n(C)c(=O)c3c2ccn3Cc2ccccc2)ccc2c1CCCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
A −78° C. solution of oxalyl chloride (1.816 mL, 20.75 mmol) in Dichloromethane (DCM) (40.0 mL) was treated slowly with DMSO (2.94 mL, 41.5 mmol) and the resultant was stirred at −78° C. for 15 minutes. A solution of 1-benzyl-5-(hydroxymethyl)-6-methyl-4-(5-methylchroman-6-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (5.1 g, 9.84 mmol) in Dichloromethane (DCM) (40.0 mL) was slowly added and the mixture was stirred at −78° C. for 40 minutes. Triethylamine (11.57 mL, 83 mmol) was then added and the mixture was stirred at −78° C. for 6 hours. The mixture was quenched with saturated sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-100% ethyl acetate/hexanes) to give 1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbaldehyde (1.53 g, 3.71 mmol, 35.8% yield). 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.45 (s, 1H), 7.41-7.24 (m, 5H), 7.06 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.02 (d, J=2.9 Hz, 1H), 6.00-5.93 (m, 1H), 5.88-5.78 (m, 1H), 4.21 (t, J=5.0 Hz, 2H), 3.95 (s, 3H), 2.70 (t, J=6.4 Hz, 2H), 2.18-2.07 (m, 2H), 1.98 (s, 3H); LC/MS (m/z) ES+=413 (M+1).
Reaction SMILES: C(Cl)CCl.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH2:26][NH:27][CH3:28].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[CH3:28][N:27]([CH2:26][C:18]1[N:17]([CH3:16])[C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13](=[O:15])/[CH:12]=[CH:11]/[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)/C=C/c1cccnc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cccnc1
Reaction time: 8 h
Yield: 40.2 %

Procedure:
EDC (0.22 g, 1.14 mmole) was added to a solution of trans-3-(3-pyridyl)acrylic acid (0.17 g, 1.14 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (0.20 g, 1.15 mmole), and HOBt.H2O (0.15 g, 1.11 mmole) in DMF (10 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) followed by preparative TLC (3% MeOH/CH2Cl2) gave the title compound (0.14 g, 40%) as a white solid: 1H NMR (360 MHz, CDCl3) indicated an approximately 8:1 mixture of amide rotamers; for the major rotamer. δ 8.79 (s, 1H), 8.59 (d, J=3.9 Hz, 1H), 7.84 (d, J 7.6 Hz, 1H), 7.76 (d, J=15.5 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.38-7.48 (m, 2H), 7.19-7.27 (m, 1H), 7.08-7.17 (m, 1H), 6.98 (d, J=15.5 Hz, 1H), 6.51 (s, 1H), 4.94 (s, 2H), 3.73 (s, 3H), 3.09 (s, 3H); MS (ES) m/e 306 (M+H)+. Anal. Calcd for C19H19N3O. 0.20 H2O: C, 73.86; H, 6.33; N, 13.60. Found: C, 73.52; H, 6.32; N, 13.43.
Reaction SMILES: [OH2:1].Cl.[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH3:9][C:3]1[CH:8]=[CH:7][C:6]([C:4]2[C:3]([C:9]([OH:1])=[O:1])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:5][CH:4]=1
Reactant: O
Reactant: Cc1ccccc1
Agent: Cl
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 170 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
The resulting reaction solution was stirred at 170° C. for 8 hours, and then cooled to 90° C. To this reaction solution was added dropwise 177.5 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added 66.6 g of toluene, and 52.64 g (505.3 mmol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75° C. to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand to separate into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate, and then gradually cooled to allow sedimentation of white crystals of 4′-methylbiphenyl-2-carboxylic acid. The temperature was lowered to 0° C., and its temperature was maintained for one hour, and then the crystals were filtered. After the crystals were washed with 20 g of toluene at 0° C., the crystals were air-dried to give 44.1 g of white crystals of 4′-methylbiphenyl-2-carboxylic acid (yield: 90.4% based on 2-cyano-4′-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.1° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:38])[C:9]1=[O:39])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:39])[N:10]([CH3:38])[C:11]=3[C:17]([CH3:18])=[C:16]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(c(C)c(-c3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2cccc(OC(F)(F)F)c2)n(Cc2ccc(Cl)cc2)c2c(=O)n(CCCO)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1,7-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (120 mg, 0.212 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (17.9 mg, 0.425 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1,7-dimethyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4 (3H,5H)-dione (15 mg, 27% yield) as a white solid. 1H NMR (CDCl3) δ: 7.49 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.13 (dd, J=16.3, 8.0 Hz, 3H), 7.04 (s, 1H), 6.71 (d, J=8.4 Hz, 2H), 5.46 (s, 2H), 4.31-4.15 (m, 2H), 3.74 (s, 3H), 3.65 (s, 1H), 3.50 (s, 2H), 2.20 (s, 3H), 1.98-1.81 (m, 2H). LCMS: MH+ 522 and TR=3.111 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=O)=[N:6][C:7]=1[CH3:8].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C=O)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A 250 mL round-bottom flask was charged with 5-bromo-6-methylpyridine-2-carbaldehyde (4.90 g, 24.6 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (4.60 g, 24.7 mmol, 1.01 equiv), 1,2-dichloroethane (150 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (15.6 g, 73.6 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with water (50 mL), extracted with dichloromethane (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (30/70) to provide 7.80 g (82% yield) of tert-butyl 4[(5-bromo-6-methylpyridin-2-yl)methyl]piperazine-1-carboxylate as a light yellow solid. LCMS (ESI, m/z): 370 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.ON1C2C=CC=CC=2N=N1.[ClH:53]>C(#N)C.C(O)C.CC(O)C>[ClH:53].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:40](=[O:41])[CH2:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH3:29])[CH:31]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)O
Solvent: CCO
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cc3cn(C)c4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridine 3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), 1-methyl-3-indoleacetic acid (0.27 g), and 1-hydroxybenzotriazole (HOBT) (0.24 g) in acetonitrile (10 ml), N-(3-dimethylaminopropyl)-NT-ethylcarbodiimide hydrochloride (WSC) (0.30 g) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1.1 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.26 g) as a pale orange white amorphous.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[C:18]([C:14]#[C:13][C@@H:12]2[CH2:11][C@H:10]([OH:15])[CH2:9][NH:8]2)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: C#C[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3C[C@H](O)CN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (3S,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (132 mg, 0.62 mmol) (Example 103A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated, and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 4 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.2 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(2S,4S)-(4-hydroxy-pyrrolidin-2-yl)-ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 58%).
Reaction SMILES: [NH2:1][OH:2].C1COCC1.Cl.[CH3:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([Cl:31])=[O:30])=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH3:11].CC(C)=O>C(#N)C>[ClH:31].[CH3:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([NH:1][OH:2])=[O:30])=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH3:11]
Reactant: NO
Reactant: CN(C)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Cl)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CC(C)=O
Product: CN(C)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1
Temperature: 9 °C
Reaction time: 0.5 h

Procedure:
A second reaction vessel was charged with aqueous hydroxylamine (50%, 42.8 kg, 647 mol) and THF (40.0 L). The above prepared solution of (E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acryloyl chloride hydrochloride was added at 18-30° C. over a period of 2-4 h. After stirring for 20-40 min, acetone (47.6 L, 647 mmol) was added at 17-25° C. within 45-90 min. The reaction mixture was stirred for 30 min and acetonitrile (570.0 L) was added over a period of 1-2 h. The suspension was stirred at 17-25° C. for at least 4 h, cooled to 5-13° C. and stirred for 1-2 h. The solid was centrifuged and was used without further drying in the subsequent free basing step.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[N:16][CH:17]=2)[CH2:7]1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][NH2:35].C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:27][N:2]([CH3:1])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:35][O:34][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)=[O:21])=[N:16][CH:17]=2)[CH2:7]1
Reactant: NOC1CCCCO1
Reactant: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)O)cn2)C1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.4 %

Procedure:
To a mixture of crude (2E)-3-[5-({(3R)-1-[2-(dimethylamino) benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylic acid (311 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (108 mg), and HOBT (125 mg) in DMF (2.4 mL) was added WSCD (164 uL), which was stirred at room temperature for 17 hours. To the resultant was added saturated NaHCO3 aq. The mixture was extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-[5-({(3R)-1-[2-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (195 mg) as a yellow amorphous.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([C:9](=O)[CH3:10])[C:5](F)=[CH:6][CH:7]=1.O.[NH2:14][NH2:15].O.[CH2:17](O)CCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[C:9]([CH3:10])[N:14]([CH3:17])[N:15]=2)[C:3]=1[F:12]
Reactant: NN
Reactant: CCCCO
Reactant: CC(=O)c1c(F)ccc(Br)c1F
Solvent: O
Product: Cc1c2c(F)c(Br)ccc2nn1C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-bromo-2,6-difluorophenyl)ethanone (4.25 g) in n-butanol (50 ml) was added hydrazine monohydrate (1.06 ml) at room temperature, and the mixture was heated under reflux for 20 hr. The reaction mixture was cooled, and added to water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). The residue was dissolved in ethyl acetate (50 ml), trimethyloxonium tetrafluoroborate (4.01 g) was added at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was added dropwise to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (224 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:15][CH2:14][N:13]3[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:6][C:5]=2[O:4]1.CN(C=[O:36])C>>[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:16](=[O:36])[C:15]=4[CH2:14][N:13]3[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:6][C:5]=2[O:4]1
Reactant: CN(C)C=O
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)N(Cc1ccncc1)CC3
Agent: [H-]
Agent: [Na+]
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(Cc1ccncc1)C2

Procedure:
Following the same procedure as outlined in Example 21, sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1-(3,4-methylened ioxyphenyl)-2-(pyridin-4-yl)methyl-2,3,4,9-tetrahydro-1H-β-carboline (192 mg, 0.50 mmol) (prepared as in Example 15) in DMF (10 mL, anhydrous) were reacted to yield the product as a white solid.